Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH2:9]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[NH:27][C:26]3[CH:36]=[CH:37][CH:38]=[N:39][C:25]2=3)=[O:23])[CH2:17][CH2:16]1)[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3]([N:11]([CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[NH:27][C:26]3[CH:36]=[CH:37][CH:38]=[N:39][C:25]2=3)=[O:23])[CH2:17][CH2:16]1)=[O:4]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CCNCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1)C(=O)C(C)(C)CC
Temperature: 50 °C

Procedure:
1.48 g (0.01 mol) of 2,2-dimethylbutyric acid chloride dissolved in 20 ml of tetrahydrofuran are added dropwise, with stirring, at ambient temperature, to a solution of 4.2 g (0.01 mol) of 5,11-dihydro-11-[[4-[3-(ethylamino)propyl]-1-piperidinyl]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 2 ml of triethylamine in 150 ml of tetrahydrofuran. In order to complete the reaction the solution is stirred for a further hour at 50° C. After cooling, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness using a rotary evaporator in a water jet vacuum. In order to purify it the residue is dissolved in ethyl acetate. The ethyl acetate solution is extracted twice with 10% hydrochloric acid, the organic phase is separated off and the aqueous phase is made alkaline by the addition of concentrated ammonia. Then the aqueous phase is extracted twice with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated to dryness in vacuo. The residue obtained is crystallised by digesting it in ethyl acetate. Colourless crystals are obtained of m.p. 136°-138° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14]Br)[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](CCBr)CN1C(=O)OC(C)(C)C
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)OCC

Procedure:
A mixture of 0.60 g of cis methyl N-t-butoxycarbonyl-4-(2-bromoethyl)pyrrolidine-2-carboxylate and 3 ml triethyl phosphite is refluxed for 2 hours. The excess triethyl phosphite is distilled off under vacuum and the residue is flash chromatographed with methylene chloride/methanol (95:5) to afford cis methyl N-t-butoxycarbonyl-4-(2-di-ethylphosphonoethyl)pyrrolidine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[CH3:22].C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([C:7]1[C:8]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([F:15])[CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
Compound A (80.0 g, 311 mmol) and 3-fluoro-4-methylphenylboronic acid (52.7 g, 342 mmol) were suspended in isopropyl alcohol (260 mL, 3.5 mol). A solution of sodium carbonate (56.1 g, 529 mmol) in water (260 mL, 15 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (3.6 g, 3.1 mmol) was then added and the mixture was stirred at 90° C. for 17 hours. The mixture was concentrated under reduced pressure and suspended in water (200 mL). The aqueous phase was extracted with EtOAc (600 mL) and separated. The organic phase was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (4-6% 5×120 g column) to yield compound B as a clear oil (68.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:27]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNCC4)no2)cc1Cl
Product: Cl
Yield: 199.3 %

Procedure:
1,1-Dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 17) (260 mg, 0.537 mmol) was dissolved in DCM (20 ml) and treated with trifluoroacetic acid (2 ml, 26.0 mmol). The resulting mixture was heated at reflux for 1 hour then evaporated. The resulting residue was partitioned between DCM (10 ml) and 2N NaOH (10 ml). The DCM layer was collected, dried (hydrophobic frit) and evaporated. The free-base was dissolved in 4M HCl in dioxane and evaporated to give the HCl salt, 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (225 mg, 0.535 mmol, 100% yield) as an off-white powder. δH (400 MHz, CDCl3) 10.10 (2H, br.s), 8.18 (1H, s), 8.02 (1H, d), 7.82-7.80 (1H, m), 7.33-7.22 (2H, m), 7.05 (1H, d), 5.30 (2H, s), 4.76-4.64 (1H, m), 3.8-3.65 (2H, m), 3.48-3.3 (4H, m), 1.45 (6H, d); MS (ES) C21H2235ClN3O2 requires 383; found 384 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH3:8])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1)=O.[H-].[Na+].CI.O.CN(C)[CH:27]=[O:28]>>[CH:27]([C:6]1[S:7][C:3]([CH3:1])=[C:4]([CH2:5][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1)=[O:28]
Reactant: Cc1sc(C=O)cc1NC(=O)OCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1sc(C=O)cc1CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a solution of benzyl (5-formyl-2-methyl-3-thienyl)carbamate (1.6 g) in N,N-dimethylformamide (20 mL) was slowly added sodium hydride (60%, oily, 0.3 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (0.47 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give benzyl (5-formyl-2-methyl-3-thienyl)methylcarbamate (0.72 g, yield 43%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].[CH3:31][CH2:32][N:33]([CH2:36]C)[CH2:34][CH3:35].[N-:38]=[C:39]=[O:40].CCOC(C)=O>C1COCC1>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@@H:9]3[NH:8][C:39]([N:38]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:40])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: [N-]=C=O
Reactant: CCN(CC)CC
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)N[C@H]2c3ccccc3C[C@@H]2NC(=O)c2cc3sc(Cl)c(Cl)c3[nH]2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-[(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetic acid salt (0.5 mmol) and Et3N (1.0 mmol) were dissolved in dry THF (5 mL), the appropriate isocyanate (1.0 mmol) was added and the reaction stirred at ambient temperature for 20 hours. EtOAc (15 mL) was added and the mixture washed with water (2×5 mL) brine (5 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound as a foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=3)=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: N#Cc1ccc(Sc2ccc(CO)cc2)cn1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Product: CC(=O)c1ccc(OCc2ccc(Sc3ccc(C#N)nc3)cc2)c(C)c1O
Yield: 64.7 %

Procedure:
Using the method of Preparation 166 using 5-(4-(hydroxymethyl)phenylthio) picolinonitrile (1.90 g, 7.84 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.30 g, 7.84 mmol) affords the title compound (1.98 g, 65%). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: Clc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 60 %

Procedure:
3.85 g (30 mmol) 5-chloroindole was treated with 6.84 g (40 mmol) benzylbromide, 1.97 g (30 mmol) potassium hydroxide (85% powdered in mortar) and 0.25 g (1 mmol) 18-crown-6 as described in Synthesis 1979 p. 618, giving 4.35 g (60%) 5-chloro-1-benzyl-1H-indole, yellow oil, MS (Ei 70 eV) m/Z M+241.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3]Br.[SH:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>CN(C)C=O>[C:5]1([CH:2]2[S:11][C:12]3=[N:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[N:13]3[CH2:3]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: BrCC(Br)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(C2Cn3c(nc4ccccc43)S2)cc1
Temperature: 100 °C

Procedure:
(1,2-Dibromoethyl)benzene (21 g) was treated with 2-mercaptobenzimidazole (17 g) in dimethylformamide (100 ml) and the mixture was heated at 100° C. for 36 hours. On cooling, the solid material was removed by filtration and recrystallised from methanol and ethyl acetate to give the title compound as the hydrobromide salt (13.68 g). mp 207°-210° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)C>[NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([O:6][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Yield: 78 %

Procedure:
The tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate was prepared as follows. 10 g (42 mmol) of (S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4 in an autoclave under an N2 pressure of 20 atm for 3 days. Excess isobutylene was blown out and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2× using 100 ml of diethyl ether each time. The combined organic phases were washed with 2×100 ml of water and dried over Na2SO4. After removal of the solvent in vacuo, 9.58 g (78%) of tert-butyl (S)-3-amino-2-benzyloxycarbonylaminopropionate were obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH3:19])[N:7]2[CH:16]1[CH2:18][CH2:17]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH3:19])[N:7]2[CH:16]1[CH2:17][CH2:18]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c(C)n(C3CC3)c12
Reactant: NCCNc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c(C)n(C3CC3)c12
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxoquinoline-3-carboxylic acid (140 mg, 0.432 mmol), N-2-pyridyl-1,2-ethanediamine (88.9 mg, 0.648 mmol) and triethylamine (0.0903 mL, 0.648 mmol) in DMSO (4 mL) was stirred at 100° C. for 2 h. To the reaction mixture, water and NH4Cl was added to neutralize and the suspension was stirred for 30 min. The crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the sovent was removed in vacuo. The crude product was purified by preparative thin layer chromatography (Hexane:EtOAc 1:4) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-2-methyl-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (79.9 mg, 42%) as a yellow amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH2:18]>N1C=CC=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH2:6][CH2:5][N:4]([S:14]([C:11]3[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=3)(=[O:15])=[O:18])[CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CNCCN1
Reactant: O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1

Procedure:
To a solution of 0.79 g (9.16 mmol) of piperazine in dry pyridine (20 ml) was added 5.15 g (20.15 mmol) of 4-bromobenzenesulfonyl chloride in an atmosphere of argon, and the mixture was allowed to react at 0° C. for 3 hours. To the solution was added water followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 4.37 g (8.34 mmol) of N,N'-bis(4-bromobenzenesulfonyl)piperazine.
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:10]=2[O:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1COCC1.CN(C=O)C.ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10]3[O:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:14])[C:18]=3[C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OC(C)(C)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1Cc1ccc(C(C)C)cc1)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a solution of 2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic acid obtained in Reference Example 156 (5.55 g, 16.3 mmol) in THF (50 mL) was added dropwise oxalyl chloride (2.13 mL, 24.5 mmol) with ice-cooling. The mixture was stirred for 20 minutes, and DMF (3 drops) was added thereto, and the mixture was stirred with ice-cooling for 30 minutes, and then, was warmed to room temperature. The solvent was removed by concentration under reduced pressure, and to a solution of the residue in dichloromethane (50 mL) was added aluminum chloride (3.26 g, 24.5 mmol) at −78° C., and the mixture was slowly warmed to room temperature. Ice was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 3.35 g (yield 64%) of 7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3 (2H)-one as crude product. To a solution of this compound (3.35 g, 10.4 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (1.85 g, 10.4 mmol) with ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, to which water was added, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 2.76 g (yield 66%) of 5-bromo-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3 (2H)-one as crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[C:7]([Br:23])[CH:6]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].Br[C:34]1C=C(CC(OC)=O)C=C(Br)[C:39]=1OC1C=CC(N)=C(N)C=1.Cl.C(CC(=O)C)(=O)C>CO>[Br:23][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:24])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]=[C:34]([CH3:39])[NH:20][C:15]=2[CH:14]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c([N+](=O)[O-])c2)c(Br)c1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(N)c(N)c2)c(Br)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(Oc2ccc3nc(C)[nH]c3c2)c(Br)c1
Yield: 5 %

Procedure:
Methyl[3,5-dibromo-4-(4-amino-3-nitrophenoxy)phenyl]acetate (1.1 g, Example 2(b)) was treated with sodium dithionite as described in Example 2(c). The formed methyl [3,5-dibromo-4-(3,4-diaminophenoxy)phenyl]acetate was dissolved in methanol (36 mL). An aqueous solution of hydrochloric acid (35%, 2.1 mL) was added, followed by acetylacetone (0.48 g). The reaction mixture was refluxed for 5.5 hours, cooled down and the formed yellow precipitate was filtered off. After recrystallisation from ethanol, 80 mg (5%) of methyl [3,5-dibromo-4-(2-methyl-5-benzoimidazolyloxy)phenyl]acetate was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH2:11]=O>CO.O.[Pd]>[CH3:11][N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][C@@H:4]1[C:8]([OH:10])=[O:9]
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Reactant: C=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: C[C@@H]1CCN(C)[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of (2R,4R)-4-methylpiperidine-2-carboxylic acid (2 g, 13.97 mmol) in MeOH (40 mL) and water (40.0 mL) was added paraformaldehyde (2.52 g, 27.94 mmol) and Pd/C (10%) (0.8 g, 7.52 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature overnight. From TLC, the reaction was not completed. Another one equivalent of paraformaldehyde (2.52 g, 27.94 mmol) was added and the reaction mixture was stirred another 24 hours. TLC indicated the reaction was completed and reaction mixture was filtered, washed the catalyst with MeOH (2×30 mL). The filtrate was concentrated in vacuo to give crude product as a white solid, which was washed with ether (3×30 mL), dried in high vacuum overnight to yield (2R,4R)-1,4-dimethylpiperidine-2-carboxylic acid (1) (1.870 g, 85%) as a white solid. LC-MS: 158 (M+1); 1H NMR (400 MHz, D2O) δ ppm 0.97 (d, J=5.52 Hz, 3H), 1.54 (br. s, 1H), 1.71-1.87 (m, 3H), 1.91-2.07 (m, 1H), 2.84 (s, 3H), 3.13 (td, J=8.41, 3.76 Hz, 1H), 3.35 (m, 1H), 3.65 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[CH:16]=1.[ClH:23]>C1COCC1.C(OCC)(=O)C.O>[Cl:23][C:18]1[CH:19]=[CH:20][C:15]([C:14]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:13])=[CH:16][CH:17]=1
Reactant: O=C1CCc2sccc21
Reactant: COC(=O)c1cccc(Cl)c1
Reactant: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 45 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 10 mL of THF was treated with NaH (60 percent, 0.73 g, 18 mmol). After the addition of 3-Chloro-benzoic acid methyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(4-Chloro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 3.3 mmol) as brown solid in 45% yield.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:8]=[CH:9][C:10]([F:22])=[C:11]([C:13]2[C:14]([C:20]#[N:21])=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)(=[O:6])[CH3:5]>O1CCOCC1.O.O1CCOCC1>[F:19][C:16]1[CH:15]=[C:14]([C:20]#[N:21])[C:13]([C:11]2[CH:12]=[C:7]([C:4](=[O:6])[CH:5]=[O:2])[CH:8]=[CH:9][C:10]=2[F:22])=[CH:18][CH:17]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)c(-c2ccc(F)cc2C#N)c1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(F)ccc1-c1cc(C(=O)C=O)ccc1F
Temperature: 25 °C

Procedure:
Selenium dioxide (0.556 g, 5.00 mmol) dissolved in 1,4dioxane:water (4:1, 5 ml) was added in one portion to 5′-acetyl-4,2′-difluorobiphenyl-2-carbonitrile (0.92 g, 3.58 mmol) in 1,4-dioxane (10 ml) and the mixture heated at reflux for 18 h. The reaction was allowed to cool to room temperature, filtered and the filtrate evaporated to give an orange-coloured glassy solid which was used without further purification (0.97 g).